Inflammation is one of the common causes of many disorders including asthma, inflammatory bowel disease, rheumatoid arthritis, osteoarthritis, rhinitis, conjunctivitis and dermatitis. Inflammation also leads to pain. One of the major problems associated with existing treatments of inflammatory conditions is inadequate efficacy and/or the prevalence of side effects.
The enzyme cyclooxygenase (COX) converts arachidonic acid to an unstable intermediate, prostaglandin H2 (PGH2), which is further converted to other prostaglandins, including PGE2, PGF2α, PGD2, prostacyclin and thromboxane A2. Among all prostaglandin metabolites, PGE2 is particularly known to be a strong pro-inflammatory mediator, and is also known to induce fever and pain. The conversion of PGH2 to PGE2 by prostaglandin E synthases (PGES) may therefore represent a pivotal step in the propagation of inflammatory stimuli.
There are two microsomal prostaglandin E synthases (mPGES-1 and mPGES-2), and one cytosolic prostaglandin E synthase (cPGES). mPGES-1 is an inducible PGES after exposure to pro-inflammatory stimuli. mPGES-1 is induced in the periphery and central nervous system (CNS) by inflammation, and represents therefore a target for acute and chronic inflammatory disorders. PGE2 is a major prostanoid, produced from arachidonic acid liberated by phospholipases (PLAs), which drives the inflammatory processes. Arachidonic acid is transformed by the action of prostaglandin H synthase (PGH synthase, cycloxygenase) into PGH2 which is a substrate for mPGES-1, the terminal enzyme transforming PGH2 to the pro-inflammatory PGE2.
Agents that are capable of inhibiting the action of mPGES-1, and thus reducing the formation of the specific arachidonic acid metabolite PGE2, are beneficial in the treatment of inflammation. Blocking the formation of PGE2 in animal models of inflammatory pain results in reduced inflammation, pain and fever response (see, e.g., Kojima et. al., The Journal of Immunology, 2008, 180, 8361-6; Xu et. al., The Journal of Pharmacology and Experimental Therapeutics, 2008, 326, 754-63).
Osteoarthritis is a complex degenerative disease of joints characterized by progressive destruction of articular cartilage and peri-articular structures including bones, synovium, and associated fibrous joint tissues, and varying degrees of inflammation. Existing drug therapies can reduce pain associated with osteoarthritis, but may be only moderately effective over time and such therapies have a variable risk/benefit consideration. Current treatments using non-steroidal, anti-inflammatory drugs (NSAIDS) and/or Cyclooxygenase-2 inhibitors (COX-2 inhibitors) are efficacious, but can cause significant cardiovascular and gastrointestinal effects. Consequently, these classes of drugs may be contraindicated for many patients due to the patient's pre-existing or emergent cardiovascular and/or gastrointestinal conditions. Additionally, patients on these therapies can become refractory to specific drug treatments.
Thus, there still is a need for improved medications that can effectively treat musculoskeletal and connective tissue pain or inflammations and related symptoms. A medication that can provide long term control of musculoskeletal and connective tissue inflammations, inhibit further progress of existing conditions, and prevent reoccurrence of acute symptoms will have important medical significance for millions of people who suffer from these diseases
International Publication Number WO 13/186692 discloses compounds which are shown to be mPGES-1 inhibitors. The publication discloses a compound N-(4-chloro-3-(5-oxo-1-(4-(trifluoromethyl)phenyl)-4,5-dihydro-1H-1,2,4-triazol-3-yl)benzyl)pivalamide, and pharmaceutically acceptable salts thereof. International Publication Number WO 16/016861 discloses nano-particulate formulations of N-(4-chloro-3-(5-oxo-1-(4-(trifluoromethyl)phenyl)-4,5-dihydro-1H-1,2,4-triazol-3-yl)benzyl)pivalamide. The entire contents of WO 13/186692 and WO 16/016861 are hereby incorporated by reference.